Asthma is a chronic relapsing airway disease that represents a major public health problem worldwide. Intermittent exacerbations are provoked by airway mucosal exposure to pro-inflammatory stimuli, with RNA viral infections or inhaled allergens representing the two most common precipitants. This P01 is comprised of 4 synergistic, inter-related projects investigating the overall hypothesis that ROS production by the respiratory mucosa activates the innate immune response {IIR), producing airway inflammation. This mucosal-initiated airway inflammation is modulated by antioxidant proteins and products of endogenous DNA damage-repair. During the past funding period we have made significant advances in understanding how paramyxovirus (Respiratory Syncytial Virus) infections modulate reactive oxygen species (ROS) and innate signaling. In addition, we have defined the mechanisms of pollen (ragweed) intrinsic NADPH-oxidases in modulating ROS and DNA damage-repair pathways in mucosal-resident cells. Our studies will advance the field's understanding of the intricate relationships among ROS, IIR activation and airway hyperresponsiveness. Specifically, we will show how the IIR is activated by ROS to control inflammatory cytokine mRNA elongation by cyclin kinases (P1), how endogenous antioxidant gene responses are modulated by respiratory syncytial virus (P2), how ROS-induced DNA damage/repair pathways affect inflammatory responses (P3), and how ragweed pollen NADPH oxidases bound to the cell membrane via toll-like receptor {TLR) 4 induce intracellular ROS and the DNA damage/repair response (P4 ). These projects will be supported by an Administrative Core (Core A), responsible for scheduling our ongoing meetings, seminars, and interactions with two Advisory groups (Internal and External), and providing biostatistical support to the projects; and a Viral Tissue Culture and Immunoassay Core (VTCIC, Core B), an established core responsible for high-quality viral and cell culture preparations, Bio-Plex, lung function and immunoassays; both cores support all four research projects. These projects function within an established collaborative environment demonstrated by over 52 multi-authored publications, with the involvement of 22 trainees in asthma research, and supported by UTMB's Clinical and Translational Sciences Award, and NHLBI-funded Proteomics Center on airway inflammation. Our work will lay the foundation for future studies aimed at translating the findings from this project period into novel treatments for asthma.